Ciftci Halil Ibrahim, Ozturk Safiye Emirdag, Ali Taha F S, Radwan Mohamed O, Tateishi Hiroshi, Koga Ryoko, Ocak Zeynep, Can Mustafa, Otsuka Masami, Fujita Mikako
Department of Bioorganic Medicinal Chemistry, Faculty of Life Sciences, Kumamoto University.
Chemistry Department, Faculty of Science, Ege University.
Biol Pharm Bull. 2018 Apr 1;41(4):570-574. doi: 10.1248/bpb.b17-00902. Epub 2018 Jan 30.
The discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC value of 9.3 µM. In contrast, the IC against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC=8.7 µM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors.
嵌合酪氨酸激酶断裂簇区域激酶-阿贝尔森激酶（BCR-ABL）靶向药物伊马替尼的发现从概念上改变了慢性粒细胞白血病（CML）的治疗方式。然而，一些CML患者对伊马替尼表现出耐药性。为了解决这个问题，一些人工合成的杂环化合物已被鉴定为BCR-ABL抑制剂。在此，我们研究了植物来源的五环三萜皂苷元及其衍生物是否对BCR-ABL具有抑制活性。在这三种衍生物中，苄基3-羟基-23-氧代齐墩果-12-烯-28-酸酯（1c）被发现是对CML细胞系K562最有效的抗癌剂，其IC值为9.3 μM。相比之下，其对正常外周血单个核细胞的IC值为276.0 μM，显示出比伊马替尼更好的选择性。化合物1c对BCR-ABL的激酶成分阿贝尔森激酶1（ABL1）具有体外抑制活性（IC = 8.7 μM）。此外，与伊马替尼相比，化合物1c对八种激酶表现出不同的抑制谱。通过分子对接研究检测了ABL的ATP结合位点与1c之间的相互作用，其结合模式不同于伊马替尼和新一代抑制剂。此外，1c抑制了BCR-ABL的下游信号传导。这项研究表明植物提取物可能成为CML治疗的一个来源，并提供了一种克服对已知BCR-ABL抑制剂耐药性的策略。
